The aim of the present proposal is to explore the possibility that the antihistaminic properties of certain neuroleptics and antidepressants might contribute to the unwanted weight gain and obesity seen with these drugs. Further, proposed experiments will also provide basic information about the possible role of histamine (H) in appetite regulation. The proposed studies will assess the effects of two neuroleptics (clozapine and haloperidol) and two antidepressants (doxepin and desipramine) which have either very potent or very weak antihistaminic effects. Further test drugs include two "authentic" antihistaminic drugs (cyproheptadine and promethazine), as well as the histamine-specific agents histidine (which increases central histamine levels) and brocresine (which decreases central histamine levels). Both the acute and chronic effects of these drugs on food intake and body weight will be evaluated in male rats given ad libitum access to either Purina Chow or a liquid diet. The main hypothesis is that increases in food intake and body weight will be observed with those test drugs which block H receptors or decrease central H levels, while no changes, or decreases in food intake and body weight will be seen with those drugs which do not block H receptors, or which increase central H levels. A greater understanding of the mechanisms involved in drug-induced weight gain would be of clinical significance. Depending on each case, clinicians could either avoid or exploit the side effect, and use existing drugs for novel purposes. Further, patient compliance with psychiatric drug treatment might improve if weight gain is no longer a necessary consequence of drug treatment. In addition to generating clinically useful data, the present proposal could also provide basic information about the possible role of histamine in appetite regulation, and thus contribute to new ideas about the neurochemical basis for obesity.